This application seeks renewal of a program that is now in its 30th year. The proposal comprises five scientific projects focused on studies of the mechanisms of hypoxic pulmonary hypertension (PH). The proposed studies are collectively founded on the hypothesis that the pathogenesis of hypoxic PH involves both functional (vasoconstriction) and structural (vascular wall thickening) components, and that both components reflect hypoxia-induced alterations in endothelial cell (EC), smooth muscle cell (SMC), and fibroblast function. All five projects study direct effects of hypoxia on cellular function, and four examine pulmonary vascular responses in hypoxic hypertensive animals. The projects are highly interactive, both conceptually and in the performance and communication of experimental results. They share numerous experimental techniques and resources and are supported by three strong cores: administrative, animal, and tissue culture. The five projects address new and innovative hypotheses regarding the cellular mechanisms of hypoxic PH. Dr. McMurtry's Project explores the role of Rho/Rho-kinase signaling in mediating sustained hypoxic pulmonary vasoconstriction and vascular remodeling. Dr. Stenmark's Project investigates the molecular mechanisms that regulate hypoxia-induced differentiation of pulmonary artery adventitial fibroblasts into myofibroblasts. Dr. Dempsey's Project explores how neutral endopeptidase selectively suppresses hypoxia-induced pulmonary artery medial and adventitial remodeling by both peptidase-dependent and -independent mechanisms. Dr. Rodman's Project investigates in pulmonary microvascular EC the upstream and downstream signaling pathways that link cell swelling, mitogens, and hypoxia to activation of volume- regulated anion channels, gene expression, and proliferation. Dr. Klemm's Project studies the molecular mechanisms that regulate expression of the transcription factor CREB, and the mechanisms by which CREB controls PDGF/hypoxia-induced proliferation of pulmonary artery SMC. These studies will provide new insights into the cellular and molecular mechanisms of hypoxic pulmonary vasoconstriction and vascular remodeling. This information will hopefully lead to novel and more effective therapy for PH.